The goals of this project are to characterize severe chronic infections with Epstein Barr Virus (EBV) and other lymphoproliferative disorders. and to elucidate multiple aspects of the chronic fatigue syndrome which was, earlier, considered to be related to EBV infection. To date this research project has involved about 250 patients. Included are 7 patients who were diagnosed with severe chronic EBV infections on the basis of clinical, histological, molecular and serologic features. We continue to examine immunologic features of patients with severe chronic EBV-associated lymphoproliferation and explore treatments. Acyclovir, alpha and gamma interferons proved of little value, but immunosuppressive therapies are being used with good long-term results. Detailed immunologic, neurologic, endocrinologic and psychologic studies are being conducted on selected patients with chronic fatigue. To date, we still have no consistent laboratory abnormality that permits a clear diagnosis of the chronic fatigue syndrome, however, we have been pursuing the basis and meaning of group abnormalities in neuropsychiatric, immune and endocrine systems. A series of studies of the pituitary-adrenal responsiveness to corticotropin releasing hormone and ACTH and of neuropeptide and catechol levels in spinal fluid suggest deficient central CRH release. Since CRH induces CNS arousal, these neuroendocrine findings suggest a new mechanism whereby the lethargy of chronic Fatigue Syndrome patients may be explained. We are pursuing these observations in a new series of studies and a fresh patient cohort. Arginine-Vasopressin infusions have been given to 24 patients and 20 controls to stimulate and test the HPA axis. The results will be available in late FY94. Forty- five patients were enrolled already in a placebo-controlled trial of hydrocortisone treatment. It should permit us to test the hypothesis that corticosteroid deficit leads to symptoms. We also recognized discrete abnormalities in CFS patient lymphocyte phenotype and in vitro responsiveness to mitogens in patterns suggesting mild immune activation. There is a reduction in naive (CD4xCD45RA) t Cells and an increase in memory (CD4XCD45RO) T cell bearing adhesion markers (LFA3, CD29, etc.). We have begun to pursue these findings in several other laboratory studies involving purified cell populations from patients and controls and in patients with acute influenza. A vigorous, multidisciplinary approach to the syndrome continues.